Therapy of Murine Aspergillosis with Amphotericin B in Combination with Rifampin or 5-Fluorocytosine

Arroyo, Julio C.; Medoff, Gerald; Kobayashi, George S.

doi:10.1128/aac.11.1.21

Cited by 93 publications

(22 citation statements)

References 18 publications

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“…Mice challenged intravenously with A. fumigatus and treated simultaneously with amphotericin B and either flucytosine or rifampin had significantly improved survival rates compared with the results seen with any monotherapy (6). Flucytosine also augmented the activity of both amphotericin B and itraconazole when administered in mice intravenously challenged with A. fumigatus (157).…”

Section: (D) Other Combinationsmentioning

confidence: 68%

“…We concur that single-agent therapy in most cases of invasive candidiasis and candidemia will most likely be the treatment of choice. Combination therapy may be (58) Results differ between studies and are variable amongst strains in same study (58,95), different methodologies and doses employed Mice (6, 157) and rats (187) Improved survival (6,157) Improved survival with 5FC ϩ AmB in mouse model (6). No survival benefit with 5FC ϩ AmB vs. AmB alone in steroid-suppressed rats (187).…”

Section: (D) Other Combinationsmentioning

confidence: 99%

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Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

487

368

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5 RATIONALEThe availability of new antifungal agents with novel mechanisms of action has stimulated renewed interest in combination antifungal therapies. In particular, and despite the limited clinical data, the high mortality of mold infections and the relatively limited efficacy of current agents have produced significant interest in polyene-, extended-spectrum azole-, and echinocandin-based combinations for these difficult-to-treat infections. With the recent publication of the first large randomized trial of antifungal combination therapy to be conducted in two decades (166) and the rapid proliferation of new in vitro and in vivo data on antifungal combinations, we have sought to review the recent work and future challenges in this area.The focus of this review is on the efficacy of antifungal drugs in combination with respect to the extent or rate of killing of the fungal pathogen, although other potential interactions (such as pharmacokinetic drug interactions) can impact efficacy when these agents are used together. The value of giving two drugs because each is separately effective against a group of organisms exhibiting a variety of types of resistance is not specifically discussed, but this also is an obvious and straightforward reason to use a combination of agents.It cannot be simply assumed that the use of two or more effective drugs with different mechanisms of action will produce an improved outcome compared to the results seen with a single agent. Combination antifungal therapy could reduce antifungal killing and clinical efficacy, increase potential for drug interactions and drug toxicities, and carry a much higher cost for antifungal drug expenditures without proven clinical benefit (106). Thus, it is important to critically evaluate the role of combination therapy as new data become available.Conceptual models and terminology. Methods for studying antifungal combinations in vitro and in vivo have differed considerably over time and among investigators. These tools do not differ with respect to their application to combination antibacterial or antiviral therapies and have been discussed extensively and elegantly in the landmark 1995 review by Greco (79). In brief, all approaches to evaluating combinations can be reduced to two elements: (i) a conceptual model for predicting the expected result for a combination and (ii) a set of phrases used to categorize results that are better than expected, worse than expected, or as expected. Although many subtle variations are possible, the underlying mathematical model is based on either the assumption of additive interactions or the assumption of probabilistic (multiplicative) interactions. On the basis of the terminology employed by the author who first carefully described each of these models, the two models can be usefully referred to as the Loewe additivity model and the Bliss independence model (79).The terminology used to place results into interpretive categories is often the subject of debate and confusion. Greco et al. (79) have proposed a set ...

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Section: (D) Other Combinationsmentioning

confidence: 68%

Section: (D) Other Combinationsmentioning

confidence: 99%

Combination Antifungal Therapy

Johnson

MacDougall

Ostrosky-Zeichner

et al. 2004

Antimicrob Agents Chemother

487

368

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“…Flucytosine, when used alone, has poor activity in vitro as well as in vivo against experimental aspergillosis (34). Nevertheless, the combination of flucytosine with amphotericin B or azoles has been shown to be additive to synergistic in vitro and in animal models of aspergillosis (4,34,35). Moreover, use of this combination has been advocated in some particularly difficult cases, such as central nervous system infections, due to the favorable pharmacokinetics properties of flucytosine.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of Double and Triple Combinations of Antifungal Drugs against Aspergillus fumigatus and Aspergillus terreus

Dannaoui

Lortholary

Dromer

2004

Antimicrob Agents Chemother

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Microdilution broth checkerboard techniques based on the National Committee for Clinical LaboratoryStandards methodology were used to study double and triple antifungal combinations against clinical isolates of Aspergillus fumigatus and A. terreus. The influences of the end-point definition (partial or complete inhibition) and the mode of reading (visually or spectrophotometrically) were determined. Interactions between antifungal drugs were also evaluated by agar diffusion tests. Combinations of caspofungin with either amphotericin B or voriconazole were additive for all the isolates, and antagonism was not observed. The interaction between caspofungin and flucytosine was synergistic for 62% of the isolates. In contrast, the interaction between voriconazole and flucytosine was never synergistic and antagonism was noted for 93% of the isolates. The triple combination of caspofungin with flucytosine and amphotericin B was synergistic for all the isolates tested. The triple combination of caspofungin with flucytosine and voriconazole was also mostly synergistic; but complex interactions were obtained for some isolates, with synergy or antagonism depending on the concentrations of caspofungin and voriconazole. Analysis of the influence of the reading technique on the results showed that spectrophotometric reading was a good alternative to the recommended visual reading. The results of these in vitro tests suggest that the activity of flucytosine as part of a double combination with caspofungin and as part of a triple combination with caspofungin and amphotericin B against Aspergillus spp. warrants further investigations. Animal studies are needed to evaluate the in vivo efficacies of these combinations.Invasive aspergillosis is an increasing problem that occurs primarily in immunocompromised patients (11). The mortality rate is particularly high in bone marrow transplant recipients and patients with disseminated infections (22). Until recently, amphotericin B and itraconazole were the drugs of choice for the treatment of these infections (44). Nevertheless, the overall success rate has been low, and recent reports of de novo and acquired resistance of Aspergillus fumigatus clinical isolates to itraconazole (7, 13) as well as in vivo resistance to amphotericin B (18) complicate the management of invasive aspergillosis. Moreover, some Aspergillus species such as Aspergillus terreus are less susceptible to amphotericin B (8). New drugs with activity against Aspergillus spp. include voriconazole and caspofungin. However, their therapeutic efficacies remain limited, with response rates of 45% for caspofungin in refractory cases

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“…In 92% (36 of 39) Aspergillus strains from one study, amphotericin and rifampin were synergistic (70). A single animal model has examined the combination of amphotericin B and rifampin (17), and synergy was reported in the instance studied. Terbinafine and itraconazole were synergistic for all four strains tested in one small study (268) and were additive or synergistic for all nine strains in another study (211).…”

Section: In Vitro and Animal Studies Utilizing Combinations Of Antifumentioning

confidence: 99%

AspergillusInfections in Transplant Recipients

2005

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Aspergillus infections are occurring with an increasing frequency in transplant recipients. Notable changes in the epidemiologic characteristics of this infection have occurred; these include a change in risk factors and later onset of infection. Management of invasive aspergillosis continues to be challenging, and the mortality rate, despite the use of newer antifungal agents, remains unacceptably high. Performing molecular studies to discern new targets for antifungal activity, identifying signaling pathways that may be amenable to immunologic interventions, assessing combination regimens of antifungal agents or combining antifungal agents with modulation of the host defense mechanisms, and devising diagnostic assays that can rapidly and reliably diagnose infections represent areas for future investigations that may lead to further improvement in outcomes

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Therapy of Murine Aspergillosis with Amphotericin B in Combination with Rifampin or 5-Fluorocytosine

Cited by 93 publications

References 18 publications

Combination Antifungal Therapy

Combination Antifungal Therapy

In Vitro Evaluation of Double and Triple Combinations of Antifungal Drugs against Aspergillus fumigatus and Aspergillus terreus

AspergillusInfections in Transplant Recipients

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